Mechanistic role of GNE-987 targeting BRD4-HCP5 axis in pediatric T-cell acute lymphoblastic leukemia.

This study aims to explore the mechanism of action of the Bromodomain-containing protein 4 (BRD4) inhibitor GNE-987 in the treatment of pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL), focusing on its effect in inhibiting T-ALL cell proliferation by activating the HLA Complex P5 (HCP5) Super-enhancer. Through bioinformatics approaches (including weighted gene co-expression network analysis and least absolute shrinkage and selection operator regression analysis), key factor BRD4 was identified from the Gene Expression Omnibus database, along with its related regulatory genes and Super-enhancer. In vitro experiments validated the regulatory effects of GNE-987 on the expression of BRD4 and HCP5, and its impact on T-ALL cell proliferation, colony formation, and apoptosis was assessed. Animal experiments further confirmed the efficacy of GNE-987 in inhibiting T-ALL progression by regulating HCP5. The results demonstrated that GNE-987 significantly enhances the activity of the HCP5 Super-enhancer and inhibits T-ALL cell proliferation while promoting apoptosis by downregulating BRD4. This study suggests that BRD4 and HCP5 are potential therapeutic targets for T-ALL, and GNE-987 provides a novel therapeutic strategy by targeting this regulatory axis, laying the foundation for precision therapy in T-ALL.